Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the expansion mutation.

Unlabelled: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum.

Objectives: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 () hexanucleotide repeat expansion, the most important genetic cause in both diseases.

Methods: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in . Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes.

Results: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was , with three mutation carriers (one of them also harboured a mutation). We also detected probable pathogenic genetic alterations in , and and possible pathogenic mutations in and .

Conclusion: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with , and to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the expansion mutation, regardless of family history of disease.